This proposal is the second resubmission of one reviewed in June 1998. The conceptual framework guiding the proposed research is that the biophysical properties of different LTP mechanisms should be reflected in different aspects of learning and memory. The PI has made important contributions toward understanding these, as well as the cellular and biological properties of LTP, including the recent discovery of an NMDA receptor independent form of LTP in the Schaffer collateral-CA1 synapse (Grover & Teyler, Nature, 1990). The PI now proposes to investigate the links between learning and memory and the cellular and synaptic mechanisms of LTP.The PI discovered a form of long-term potentiation (LTP) that is independent of NMDA receptors. This form of LTP is induced by 200 Hz stimulation through voltage dependent calcium channels, and contributes to the LTP observed in typical in vitro and in vivo experiments (i.e. 100 Hz stimulation). In contrast to NMDA receptor-dependent LTP, which is induced quickly and decays, voltage-dependent calcium channel LTP (vdccLTP) can be induced in the presence of NMDA receptor antagonists, builds up slowly (~20 minutes) and decays slowly (no change > 10 h in vitro). The two patterns of stimulation are differentially sensitive to different enzymatic poisons: Serine/threonine kinase poison H-7 inhibits PKC, PKA, PKG, and CamKII, and prevents NMDA-dependent LTP induction (25Hz tetanus); tyrosine kinase poisons (e.g. genistein and lavendustin A) did not significantly attenuate 25Hz LTP induction, but prevented the vdccLTP (200Hz stim) from lasting more than 80 minutes. The proposed research will explore the relationship between learning and memory and the mechanisms underlying these two forms of plasticity. Specifically, the PI will test the effects of drugs that selectively block either voltage-dependent or NMDA receptor dependent LTP on memory performance in the radial maze.To test the hypothesis that vdccLTP is required for long-term memory retention, whereas NMDA receptor-dependent LTP is required for the acquisition of shorter-term reference memory, rats will be trained and tested in the 4/8 task on a radial maze. In this task, food is placed in 4 of the 8 arms of the maze at the start of each trial without replacement, and the task for the rat is to enter each of these baited arms once to get the food most efficiently. Entries into arms that never have food define reference memory errors, and repeated entries into arms with food within a trial define working memory errors (episodic memory). Hippocampal lesions impair acquisition of both working and reference memory in this task, but lesions given after training impair only the working memory component. Two major unanswered questions remain: 1. How does the within-trial working memory persist when NMDA receptors are blocked? 2. How and where in the brain is the long-term reference memory stored? The proposal focuses on the 2nd of these questions. NMDA receptor antagonists and voltage-dependent calcium channel LTP blockers will be given, alone and in combination, to behaving rats. In separate experiments, the drugs will be given systemically and into the hippocampus directly. Dose/response curves for the effects of the drugs on LTP induction will be tested in vivo. The hypothesis is that voltage-dependent LTP is required for long-term memory retention, whereas NMDA receptor dependent LTP is required for the shorter-term acquisition of reference memory. The drugs will also be given in combination.